Antimicrobial peptides are natural antimicrobial materials involved in innate immunity mechanisms in vivo, and low-molecular weight peptide materials that retain antimicrobial activities against various microorganisms including bacteria, fungi, and viruses and induce local biophylaxis and systemic immune response. The antimicrobial peptide generally has an amphipathic structure, and according to antimicrobial mechanism thereof, a cation part thereof binds to an anionic phospholipid included in a cell membrane of the microorganism to break the cell membrane of the microorganism.
Defensins are one of the antimicrobial peptides that have been most studied, and are largely classified into α-defensin and β-defensin depending on structural characteristics thereof. β-defensin is a peptide material that is expressed in mucous epithelium such as skin, lungs, organs, kidneys, reproductive organs, etc. Until now, 6 sorts of human β-defensins, human β-defensin-1 (hBD-1), human β-defensin-2 (hBD-2), human β-defensin-3 (hBD-3), human β-defensin-4 (hBD-4), human β-defensin-5 (hBD-5), and human β-defensin-6 (hBD-6) have been separated and identified. In particular, while hBD-1 is uniformly expressed in epidemic cells, hBD-2 is increasingly expressed at an infected region or a physically damaged region and has been known to play an important role in controlling a systemic immune response and an inflammatory response. In addition, it has been recently reported that hBD-3 is very highly expressed at skin lesion regions of psoriasis patients. In recent years, it has been recently known that β-defensins are involved in not only local phylaxis but also acquired immunity resulting from chemotactic migration of dendritic cells, T lymphocytes, monocytes, etc.
Cathelicidins have extensive antimicrobial activities and various immunomodulatory functions. LL-37, one of the human cathelicidin degradation products, has a α-helix structure, and has extensive antimicrobial activities and inflammation modulatory functions in vivo. In other words, LL-37 exhibits direct antimicrobial activities against bacteria, fungi, viruses, etc., and chemotaxis for neutrophil, mononuclear cells, and T cells, and induces proliferation of endotheliocyte. In particular, LL-37 existing in the skin does prompt defense at the time of penetration of foreign antigens, and thus has antigen inhibitory functions (Braff M H, Bardan A, Nizet V, et al. Cutaneous defense mechanisms by antimicrobial peptides. J Invest Dermatol (2005) 125, 9).
When physical damage or infection occurs in the skin, defensin and LL-37, which are antimicrobial peptides, are secreted to induce antimicrobial activity and a systemic immune response, and particularly induce differentiation and proliferation of epidermal keratinocytes, to thereby be involved in wound healing (Niyonsaba F, Ushio H, Nakano N, et al. Antimicrobial peptides human β-defensins promote epidermal keratinocyte migration, proliferation and production of proinflammatory cytokines and chemokines. J Invest Dermatol (2007) 127, 594). Also, study results have been recently reported that expression of β-defensin-2, LL-37, etc., which are antimicrobial peptides, decreased in the skin of patients with atopic dermatitis, which is a cause of high sensitivity to staphylococcus (Ong P Y, et al. Endogenous Antimicrobial Peptides and Skin Infections in Atopic Dermatitis. The England Journal of Medicine (2002) 347, 1151-1160).
Therefore, the antimicrobial peptides play important roles in primary defense and treatment against foreign sources of infection. In particular, the antimicrobial peptides is expression-induced in the skin, thereby primarily inhibiting infection of the skin and blocking penetration of foreign sources of infection by promoting the recovery of the damaged region, and thus, play important roles in protection of skin and maintenance of skin health.
The related art reported materials promoting the secretion of antimicrobial peptides in vivo. Korean Patent Laid-Open Publication No. 10-2006-0076775 discloses that various organic acids promote β-defensin secretion and International Patent Laid-Open Publication No. WO 0168085 discloses that amino acid, isoleucine, promotes defensin secretion. However, there are limitations in that some materials have unfavorable effects and other materials induce simultaneous secretion of inflammatory cytokines as well as antimicrobial peptides. For this reason, there have been demands for compounds having superior activity of promoting secretion of antimicrobial peptide and not inducing secretion of inflammatory cytokines.
The present inventors synthesized various materials in order to produce new materials for promoting antimicrobial peptides for a long time, and conducted experiments for activities thereof. As a result, the present inventors synthesized new compounds having excellent effects in promoting the secretion of human β-defensins and LL-37 in vivo, and completed the present invention.